tbuckley/cabot-search huggingface dataset:
Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms
Authors: Shunsuke Katsuki, Prabhash K. Jha, Adrien Lupieri, Toshiaki Nakano, Livia S.A. Passos, Maximillian A. Rogers, Dakota Becker-Greene, Thanh-Dat Le, Julius L. Decano, Lang Ho Lee, Gabriel C. Guimaraes, Ilyes Abdelhamid, Arda Halu, Alessandro Muscoloni, Carlo V. Cannistraci, Hideyuki Higashi, Hengmin Zhang, Amélie Vromman, Peter Libby, C. Keith Ozaki, Amitabh Sharma, Sasha A. Singh, Elena Aikawa, Masanori Aikawa
Journal: Circulation Research (2022)

Background: Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. Methods: We used Ldlr -/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr -/- mouse macrophages. Results: In Ldlr -/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr -/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. Conclusions: Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.
Versatile Red Blood Cells for Triple‐Negative Breast Cancer Treatment via Stepwise Photoactivations
Authors: Yuanyuan Cheng, Qian Chen, Zhanyin Qian, Tianhe Shan, Liya Bai, Xiaoyu Jiang, Chunyu Li, Yinsong Wang
Journal: Advanced Healthcare Materials (2022)

Phototherapies have many advantages for triple-negative breast cancer (TNBC) treatment. However, their effects are often limited by short blood circulation time, poor tumor selectivity and weak penetration of phototherapeutic agents, and tumor hypoxia. For overcoming these limitations, a versatile biomimetic system is developed based on red blood cells (RBCs). Photothermal agent new indocyanine green (IR820) is conjugated with the cell/tissue-penetrating TAT peptide and further efficiently encapsulated into the intact RBCs by crossing cell membranes to realize the long blood circulation. Meanwhile, cyclic RGD peptide (cRGD) is linked to the surfaces of RBCs through phospholipid insertion to obtain tumor vessel-targeting ability. Photosensitizer temoporfin (mTHPC) is next loaded into the membranes of RBCs by spontaneous transferring. The acquired biomimetic system (cRGD-RBC@mTHPC/TAT-IR820) exhibits potent photodynamic performance upon 652 nm laser irradiation with the facilitation of oxyhemoglobin, which could not only trigger TAT-IR820 release but also destroy tumor vessels. TAT-IR820 penetrates deeply into tumor tissue via the mediation of TAT peptide, exerting greatly promoted photothermal ablation against TNBC upon 808 nm laser irradiation. In situ generated tumor antigens further induce robust immune responses to suppress TNBC recurrence and metastasis. In summary, this study provides a versatile biomimetic system for comprehensive TNBC treatment via stepwise photodynamic and photothermal activations.
What is hidden behind a pulmonary hypertensive, fibrotic and inflammatory phenotype?
Authors: Serge Adnot, Larissa Lipskaia, Oliver Bischof
Journal: European Respiratory Journal (2022)

<b>Cell senescence may represent a common trigger to the pulmonary hypertensive, fibrotic and inflammatory phenotype induced by AP-1 overexpression. AP-1 may embody a valuable therapeutic target for pulmonary fibrosis and pulmonary hypertension.</b>https://bit.ly/3EdMbZy
Estimating the minimal important difference in FEV<sub>1</sub>for patients with allergic bronchopulmonary aspergillosis
Authors: Ritesh Agarwal, Inderpaul Singh Sehgal, Valliappan Muthu, Sahajal Dhooria, Kuruswamy Thurai Prasad, Ashutosh Nath Aggarwal
Journal: European Respiratory Journal (2022)

<b>This study found a minimal important difference of 158 mL (or 17%) for the FEV<sub>1</sub> in patients with acute-stage allergic bronchopulmonary aspergillosis complicating asthma treated with prednisolone</b>https://bit.ly/3JvfBmI
Tom Nolan’s research reviews—20 October 2022
Authors: Tom Nolan
Journal: BMJ (2022)

The hypothesis that symptom-reporting in asthmatics does not necessarily correspond with clinical status, but is related to negative affectivity was investigated. One hundred and sixteen asthmatic patients filled out the Asthma Symptom Checklist (ASC), the Negative Emotionality Scale (NEM), and the McMaster-Asthma Quality-of-Life Questionnaire (AQLQ). The patients were grouped as either hospitalized, outpatient previously hospitalized or outpatient not previously hospitalized for asthma. Lung function data and Asthma Severity Scores (ASS) were also collected. The hospitalized group was retested after 3 months. The hospitalized group had lower AQLQ scores, higher ASS scores and worse lung function than both outpatient groups. However, the hospitalized group and the outpatients previously hospitalized group had higher ASC scores and NEM scores than the outpatients not previously hospitalized group. After discharge, when the hospitalized group had become clinically stable, their ASC and NEM scores remained comparable to those of the outpatient previously hospitalized group. Symptom-reporting in asthmatics is not necessarily in accordance with clinical status, but may be directly or indirectly mediated by personality, such as negative affectivity.
Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice
Authors: Suzanne M. Scheaffer, Diana Lee, Bradley Whitener, Baoling Ying, Kai Wu, Chieh-Yu Liang, Hardik Jani, Philippa Martin, Nicholas J. Amato, Laura E. Avena, Daniela Montes Berrueta, Stephen D. Schmidt, Sijy O’Dell, Arshan Nasir, Gwo-Yu Chuang, Guillaume Stewart-Jones, Richard A. Koup, Nicole A. Doria-Rose, Andrea Carfi, Sayda M. Elbashir, Larissa B. Thackray, Darin K. Edwards, Michael S. Diamond
Journal: Nature Medicine (2022)
Conductive fibers for biomedical applications
Authors: Leqian Wei, Shasha Wang, Mengqi Shan, Yimeng Li, Yongliang Wang, Fujun Wang, Lu Wang, Jifu Mao
Journal: Bioactive Materials (2022)

Bioelectricity has been stated as a key factor in regulating cell activity and tissue function in electroactive tissues. Thus, various biomedical electronic constructs have been developed to interfere with cell behaviors to promote tissue regeneration, or to interface with cells or tissue/organ surfaces to acquire physiological status via electrical signals. Benefiting from the outstanding advantages of flexibility, structural diversity, customizable mechanical properties, and tunable distribution of conductive components, conductive fibers are able to avoid the damage-inducing mechanical mismatch between the construct and the biological environment, in return to ensure stable functioning of such constructs during physiological deformation. Herein, this review starts by presenting current fabrication technologies of conductive fibers including wet spinning, microfluidic spinning, electrospinning and 3D printing as well as surface modification on fibers and fiber assemblies. To provide an update on the biomedical applications of conductive fibers and fiber assemblies, we further elaborate conductive fibrous constructs utilized in tissue engineering and regeneration, implantable healthcare bioelectronics, and wearable healthcare bioelectronics. To conclude, current challenges and future perspectives of biomedical electronic constructs built by conductive fibers are discussed.
Plant-derived nanovesicles: Current understanding and applications for cancer therapy
Authors: Ngoc Phung Ly, Hwa Seung Han, Myungsuk Kim, Jae Hyung Park, Ki Young Choi
Journal: Bioactive Materials (2022)

Plant-derived vesicles (PDVs) are membranous structures that originate from plant cells and are responsible for multiple physiological and pathological functions. In the last decade, PDVs have gained much attention for their involvement in different biological processes, including intercellular communication and defense response, and recent scientific evidence has opened a new avenue for their applications in cancer treatment. Nevertheless, much remains unknown about these vesicles, and current research remains inconsistent. This review aims to provide a comprehensive introduction to PDVs, from their biological characteristics to purification methods, and to summarize the status of their potential development for cancer therapy.
Restore the doctor-patient relationship in primary care, say MPs
Authors: Adrian O’Dowd
Journal: BMJ (2022)

<h3>Abstract</h3> The emergence of antibiotic resistance in human pathogens has become a major threat to modern medicine and in particular hospitalized patients. The outcome of antibiotic treatment can be affected by the composition of the gut resistome either by enabling resistance gene acquisition of infecting pathogens or by modulating the collateral effects of antibiotic treatment on the commensal microbiome. Accordingly, knowledge of the gut resistome composition could enable more effective and individualized treatment of bacterial infections. Yet, rapid workflows for resistome characterization are lacking. To address this challenge we developed the poreFUME workflow that deploys functional metagenomic selections and nanopore sequencing to resistome mapping. We demonstrate the approach by functionally characterizing the gut resistome of an ICU patient. The accuracy of the poreFUME pipeline is &gt;97 % sufficient for the reliable annotation of antibiotic resistance genes. The poreFUME pipeline provides a promising approach for efficient resistome profiling that could inform antibiotic treatment decisions in the future.
Transcription factor CASZ1 increases an oncogenic transcriptional process in tumorigenesis and progression of glioma cells
Authors: Chaofu Mao, Chengying Huang, Zhicheng Hu, Shanqiang Qu
Journal: MedComm (2022)

Abstract As a transcription factor, the role of CASZ1 in different entities is inconsistent. Glioma is one of the leading causes of cancer death worldwide. Its prognostic relevance and biological functions in glioma remain obscure. We focused on the role, mechanism, and prognostic value of CASZ1 in glioma cells. Herein, CASZ1 was identified as a novel potential oncogene in glioma tissues from GEO and TCGA datasets. CASZ1 was highly expressed in glioma tissues, predicting poor prognosis in glioma patients. Knockdown of CASZ1 inhibited proliferation and invasion in vitro, whereas upregulation of CASZ1 presented opposite results. Overexpression of CASZ1 increased transcriptional process of target gene p75NTR. CASZ1 was the potential transcriptional regulators for p75NTR. In addition, the p75NTR expression is essential for CASZ1 to exert its function as an oncogene. Our findings indicate that highly expressed CASZ1 in glioma cells acts as a pro‐oncogene factor in gliomas via regulating transcriptional process of target gene p75NTR, which was identified as an unfavorable prognostic marker in patients with gliomas. CASZ1 is expected to become a novel target for the treatment of gliomas.
Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions
Authors: Maria Thastrup, Alasdair Duguid, Christian Mirian, Kjeld Schmiegelow, Christina Halsey
Journal: Leukemia (2022)

Abstract Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2–3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear – we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.
Association of Virtual Care Expansion With Environmental Sustainability and Reduced Patient Costs During the COVID-19 Pandemic in Ontario, Canada
Authors: Blayne Welk, Eric McArthur, Alexandra P. Zorzi
Journal: JAMA Network Open (2022)

Importance There is a growing focus on environmental sustainability in health care. Objective To estimate the environmental and patient-level financial benefits associated with the widespread adoption of virtual care during the COVID-19 pandemic. Design, Setting, and Participants This population-based cross-sectional study obtained data from linked administrative databases in the universal health care system of Ontario, Canada, from March 2020 to December 2021. Participants included all people with a physician claim for at least 1 episode of virtual care. Exposures Patients were stratified by age, socioeconomic status quintiles, Charlson Comorbidity Index, and area of residence (rural or urban). Main Outcomes and Measures The primary outcomes were total travel distance and estimated travel-related carbon dioxide emissions avoided owing to virtual care visits. Different model assumptions were used to account for electric and hybrid vehicles and public transit use. The secondary outcomes were estimated patient costs (gasoline, parking, or public transit expenses) avoided. Results During the 22-month study period, 10 146 843 patients (mean [SD] age, 44.1 [23.1] years; 5 536 611 women [54.6%]) had 63 758 914 physician virtual care visits. These visits were associated with avoidance of 3.2 billion km of travel distance and between 545 and 658 million kg of carbon dioxide emissions. Patients avoided an estimated total of $569 to $733 million (Canadian [US $465-$599 million]) in parking, public transit, and gasoline costs. Carbon dioxide emission avoidance and patient cost savings were more apparent in patients living in rural areas, those with higher comorbidity, and those who were older than 65 years. Conclusions and Relevance Results of this study suggest that virtual care was associated with a large amount of carbon dioxide emissions avoided owing to reduced patient travel and with millions of dollars saved in parking, gasoline, or public transit costs. These benefits are likely to continue as virtual care is maintained as part of the health care system.
Mineralocorticoid Receptor Pathway Is a Key Mediator of Carfilzomib-induced Nephrotoxicity: Preventive Role of Eplerenone
Authors: Panagiotis Efentakis, Sofia Lamprou, Manousos Makridakis, Ioanna Barla, Panagiota-Efstathia Nikolaou, Andriana Christodoulou, Costantinos Dimitriou, Nikolaos Kostomitsopoulos, Ioannis Ntanasis-Stathopoulos, Irene Theochari, Maria Gavriatopoulou, Harikleia Gakiopoulou, Androniki Tasouli, Antonia Vlahou, Evangelos Gikas, Nikolaos Thomaidis, Meletios-Athanasios Dimopoulos, Evangelos Terpos, Ioanna Andreadou
Journal: HemaSphere (2022)

Carfilzomib is an irreversible proteasome inhibitor indicated for relapsed/refractory multiple myeloma. Carfilzomib toxicity includes renal adverse effects (RAEs) of obscure pathobiology. Therefore, we investigated the mechanisms of nephrotoxicity developed by Carfilzomib. In a first experimental series, we used our previously established in vivo mouse models of Carfilzomib cardiotoxicity, that incorporated 2 and 4 doses of Carfilzomib, to identify whether Carfilzomib affects renal pathways. Hematology and biochemical analyses were performed, while kidneys underwent histological and molecular analyses. In a second and third experimental series, the 4 doses protocol was repeated for 24 hours urine collection and proteomic/metabolomic analyses. To test an experimental intervention, primary murine collecting duct tubular epithelial cells were treated with Carfilzomib and/or Eplerenone and Metformin. Finally, Eplerenone was orally co-administered with Carfilzomib daily (165 mg/kg) in the 4 doses protocol. We additionally used material from 7 patients to validate our findings and patients underwent biochemical analysis and assessment of renal mineralocorticoid receptor (MR) axis activation. In vivo screening showed that Carfilzomib-induced renal histological deficits and increased serum creatinine, urea, NGAL levels, and proteinuria only in the 4 doses protocol. Carfilzomib decreased diuresis, altered renal metabolism, and activated MR axis. This was consistent with the cytotoxicity found in primary murine collecting duct tubular epithelial cells, whereas Carfilzomib + Eplerenone co-administration abrogated Carfilzomib-related nephrotoxic effects in vitro and in vivo. Renal SGK-1, a marker of MR activation, increased in patients with Carfilzomib-related RAEs. Conclusively, Carfilzomib-induced renal MR/SGK-1 activation orchestrates RAEs and water retention both in vivo and in the clinical setting. MR blockade emerges as a potential therapeutic approach against Carfilzomib-related nephrotoxicity.
Incidence of Emergency Department Visits for Sexual Abuse Among Youth in Hong Kong Before and During the COVID-19 Pandemic
Authors: Janet Yuen Ha Wong, Luke Y. F. Luk, Tsz Fung Yip, Teddy Tai Loy Lee, Abraham Ka Chung Wai, Joshua W. K. Ho
Journal: JAMA Network Open (2022)

This cohort study assesses the incidence of emergency department (ED) visits in Hong Kong, China, for sexual abuse among youth before and during the COVID-19 pandemic.
Trends in US Emergency Department Use After Sexual Assault, 2006-2019
Authors: Emily L. Vogt, Charley Jiang, Quinton Jenkins, Maya J. Millette, Martina T. Caldwell, Kathleen S. Mehari, Erica E. Marsh
Journal: JAMA Network Open (2022)

Importance Adult sexual assault (SA) survivors experience numerous emergent health problems, yet few seek emergency medical care. Quantifying the number and types of survivors presenting to US emergency departments (EDs) after SA can inform health care delivery strategies to reduce survivor morbidity and mortality. Objective To quantify ED use and factors that influenced seeking ED care for adult SA from 2006 through 2019. Design, Setting, and Participants This cross-sectional study used SA data from the Nationwide Emergency Department Sample from 2006 through 2019, which includes more than 35.8 million observations of US ED visits from 989 hospitals, a 20% stratified sample of hospital-based EDs. The study also used the Federal Bureau of Investigation’s Uniform Crime Reporting Program, which includes annual crime data from more than 18 000 law enforcement agencies representing more than 300 million US inhabitants. The study sample included any adult aged 18 to 65 years with an ED visit in the Nationwide Emergency Department Sample coded as SA. The data were analyzed between January 2020 and June 2022. Main Outcomes and Measures Annual SA-related ED visits, subsequent hospital admissions, and associated patient-related factors (age, sex, race and ethnicity, income quartile, and insurance) were analyzed using descriptive statistics. Results Data were from 120 to 143 million weighted ED visits reported annually from 2006 through 2019. Sexual assault–related ED visits increased more than 1533.0% from 3607 in 2006 to 55 296 in 2019. Concurrently, admission rates for these visits declined from 12.6% to 4.3%. Female, younger, and lower-income individuals were more likely to present to the ED after SA. Older and Medicaid-insured patients were more likely to be admitted. Overall, the rate of ED visits for SA outpaced law enforcement reporting. Conclusions and Relevance This cross-sectional study found that US adult SA ED visits increased from 2006 through 2019 and highlighted the populations who access emergency care most frequently and who more likely need inpatient care. These data can inform policies and the programming needed to support this vulnerable population.